Defining the role of Flt3 ligand as a biomarker of acute myeloid leukaemia and dual regulator of haematopoiesis and immunity

Acute Myeloid Leukaemia (AML) affects more than 3,000 people each year in the UK and is the most common and difficult to treat acute leukaemia in adults. FLT3 is a receptor that plays an essential role in normal blood cell development and AML. The hormone that binds FLT3, known as FLT3 ligand (FL), stimulates the growth of AML cells but the production of FL in humans in vivo is complex and not well understood.

We have previously shown that patients with AML have almost undetectable levels of FL at diagnosis. When treatment is successful, serum FL rises to a very high level but if leukaemia is resistant to treatment, then FL remains low. This observation means that potentially, a blood test for FL can determine the response of AML to treatment. Whether leukaemia responds to the first-line of therapy is a critical factor in patient survival.

There are multiple sources of FL, including specialised cells in the bone marrow stem cell niche, immune cells such as T cells, stromal cells and endothelium. In all sites, FL is synthesized as a cell-bound protein before it is cut by an enzyme and released into the circulation. It is likely that FL has two different roles: one to nourish blood stem cells, which is subverted by AML, and the other to stimulate immune cells known as dendritic cells, which also express a high level of the FLT3 receptor.

If these two different roles can be disentangled, it may may be possible to develop new AML therapy based on FL.

The first aim of my project is to determine whether FL, measured during treatment, can predict the result of the first bone marrow test to assess response. I have initiated the ARC-LITE study to collect samples from patients undergoing treatment for AML to measure FL and compare data, such as the rate of rise and peak level of FL, with bone marrow tests.

This will potentially revolutionise the care of patients with AML, providing 'real time' assessment of their progress. It will be especially useful for older patients seeking less intensive treatment with fewer hospital procedures. In the future, I plan to link ARC-LITE with national AML trials currently in set up by collaborators in the NCRI AML Working Group.

The second aim of my project is to understand the production and regulation of FL in vivo in more detail. Presently, there is no distinction between the stem cell functions of FL relevant to AML, and the immune functions of FL which may be either beneficial or harmful in the context of treatment for AML. I will study the production and regulation of FL in bone marrow, blood and skin, monitoring patients with AML, using very sensitive single cell analysis to pull apart these different functions.

This is important because it may be possible to target FL in the stem cell niche to improve treatment of AML. Conversely, changes in the level of FL that occur during leukaemia treatment may have detrimental effects on the immune system that contribute to the toxicity of chemotherapy. This aim will use state of the art technology with a unique set of samples. It is likely to generate scientific insights informing new therapeutic approaches to AML.